The present invention concerns novel compounds having vasopressin agonist activity, as well as methods of treatment and pharmaceutical compositions utilizing the same.
Vasopressin (antidiuretic hormone, ADH), a nine amino acid peptide hormone and neurotransmitter, is synthesized in the hypothalamus of the brain and is transported through the supraopticohypophyseal tract to the posterior pituitary where it is stored. Upon sensing an increase of plasma osmolality by brain osmoreceptors or a decrease of blood volume or blood pressure detected by the baroreceptors and volume receptors, vasopressin is released into the blood circulation and it activates vasopressin V1a receptors on blood vessels to cause vasoconstriction to raise blood pressure and vasopressin V2 receptors of the nephrons of the kidney to retain mainly water, and to a lesser degree electrolytes, to expand the blood volume (Cervoni P. and Chan P. S., Diuretic Agents, In Kirk-Othmer: Encyclopedia of Chemical Technology, 4th Ed., Wiley, Volume 8, 398-432, 1993.). The existence of vasopressin in the pituitary was known as early as 1895 (Oliver, H. and Schaefer, J. Physiol. (London) 18: 277-279, 1895). The determination of the structure and the complete synthesis of vasopressin were accomplished by duVigneaud and co-workers in 1954 (duVigneaud, V., Gish, D. T., and Katsoyannis, J. Am. Chem. Soc. 76: 4751-4752, 1954.).
Vasopressin V1a receptors are mediated through the phosphatidylinositol pathway. Activation of vasopressin V1a receptors causes contraction of the smooth muscle of the blood vessels so as to raise blood pressure. The actions of the vasopressin V2 receptors are mediated through activation of the adenylate cyclase system and elevation of intracellular levels of cAMP. The activation of the vasopressin V2 receptors by vasopressin or vasopressin-like (peptide or nonpeptide) compounds increases water permeability of the collecting ducts of the nephron and permits the reabsorption of a large quantity of free water. The end result is the formation and excretion of a concentrated urine, with a decrease of urine volume and an increase of urinary osmolality.
Vasopressin plays a vital role in the conservation of water by concentrating the urine at the site of the collecting ducts of the kidney. The collecting ducts of the kidney are relatively impermeable to water without the presence of vasopressin at the receptors and therefore, the hypotonic fluid formed after filtering through the glomeruli, passing the proximal convoluted tubules, the loops of Henle, and the distal convoluted tubules, will be excreted as dilute urine. However, during dehydration, volume depletion or blood loss, vasopressin is released from the brain and activates the vasopressin V2 receptors in the collecting ducts of the kidney rendering the ducts very permeable to water, and hence water is reabsorbed and a concentrated urine is excreted. In patients and animals with central or neurogenic diabetes insipidus, the synthesis of vasopressin in the brain is defective and therefore, they produce no or very little vasopressin, but their vasopressin receptors in the kidneys are normal. Because they cannot concentrate the urine, they may produce as high as 10 times the urine volume of their healthy counterparts and they are very sensitive to the action of vasopressin and vasopressin V2 agonists. Vasopressin and desmopressin, which is a peptide analog of the natural vasopressin, are being used in patients with central diabetes insipidus. Vasopressin V2 agonists are also useful for the treatment of nocturnal enuresis, nocturia, urinary incontinence and help provide the ability of the recipient to temporarily delay urination, whenever desirable.
Vasopressin, through activation of its V1a receptors, exerts vasoconstricting effects so as to raise the blood pressure. A vasopressin V1a receptor antagonist will counteract this effect. Vasopressin and vasopressin agonists release factor VIII and von Willebrand factor so they are useful for the treatment of bleeding disorders, such as hemophilia. Vasopressin and vasopressin-like agonists also release tissue-type plasminogen activator (t-PA) into the blood circulation so they are useful in dissolving blood clots such as in patients with myocardial infarction and other thromboembolic disorders (Jackson, E. K., Vasopressin and other agents affecting the renal conservation of water. In: Goodman""s and Gilman""s The Pharmacological Basis of Therapeutics, 9th ed., Eds. Hardman, Limbird, Molinoff, Ruddon and Gilman, McGraw-Hill, New York, pp. 715-731, 1996, Lethagen, S., Ann. Hematol., 69; 173-180 (1994), Cash, J. D. et al., Brit. J. Haematol. 27; 363-364, 1974., David, J-L., Regulatory Peptides, 45; 311-317, 1993, and Burggraaf, J., et al., Clin. Sci. 86; 497-503 (1994).
The following prior art references describe peptide vasopressin antagonists: M. Manning et al., J. Med. Chem., 35, 382(1992); M. Manning et al., J. Med. Chem., 35, 3895(1992); H. Gavras and B. Lammek, U.S. Pat. No. 5,070,187 (1991); M. Manning and W. H. Sawyer, U.S. Pat. No. 5,055,448(1991) F. E. Ali, U.S. Pat. No. 4,766,108(1988); R. R. Ruffolo et al., Drug News and Perspective, 4(4), 217, (May 1991). P. D. Williams et al., have reported on potent hexapeptide oxytocin antagonists [J. Med. Chem., 35, 3905(1992)] which also exhibit weak vasopressin antagonist activity in binding to V1 and V2 receptors. Peptide vasopressin antagonists suffer from a lack of oral activity and many of these peptides are not selective antagonists since they also exhibit partial agonist activity.
Non-peptide vasopressin antagonists have recently been disclosed. Albright et al. describe tricyclic diazepines as vasopressin and oxytocin antagonists in U.S. Pat. No. 20 5,516,774 (May 14, 1996); tetrahydrobenzodiazepine derivatives as vasopressin antagonists are disclosed in JP 08081460-A (Mar. 26, 1996); Ogawa, et al. disclose benzoheterocyclic derivatives as vasopressin and oxytocin antagonists, and as vasopressin agonists in WO 9534540-A; Albright, et al. disclose tricyclic benzazepine derivatives as vasopressin antagonists in U.S. Pat. No. 5,512,563 (Apr. 30, 1996); and Venkatesan, et al. disclose tricyclic benzazepine derivatives as vasopressin and oxytocin antagonists in U.S. Pat. No. 5,521,173 (May 28, 1996).
As mentioned above, desmopressin (1-desamino-8-D-arginine vasopressin) (Huguenin, Boissonnas, Helv. Chim. Acta, 49, 695 (1966)) is a vasopressin agonist. The compound is a synthetic peptide with variable bioavailability. An intranasal route is poorly tolerated and an oral formulation for nocturnal enuresis requires a 10-20 fold greater dose than by intranasal administration.
The compounds of this invention are non-peptidic and have good oral bioavailability. They are specific vasopressin V2 agonists, and have no V1a agonist effects so they do not raise blood pressure. In contrast, the prior art compounds of Ogawa, H. et al. WO 9534540-A are vasopressin/oxytocin antagonists.
This invention relates to new compounds selected from those of the general formula (I): 
wherein:
A, B, E, G are, independently, CH or nitrogen;
D is, independently, Cxe2x80x94W or nitrogen;
R1 is alkanoyl of 2 to 7 carbon atoms, a group selected from CN, COOH, 
xe2x80x83or a moiety selected from the group: 
R2, R3 and R5 are, independently, hydrogen, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, or perfluoroalkyl of 1 to 6 carbons;
R4 is hydrogen, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkoxyalkyl of 2 to 7 carbon atoms, or an acyl substituent selected from the group consisting of alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, cycloalkanoyl of 3 to 7 carbon atoms, aroyl, or arylalkanoyl;
X and Y are, independently, hydrogen, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, perfluoroalkyl of 1 to 6 carbons, alkoxyalkyl of 2 to 7 carbon atoms, halogen (including chlorine, bromine, fluorine, and iodine), alkoxy of 1 to 6 carbons, hydroxy, CF3, or perfluoroalkyl of 2 to 6 carbons;
W is hydrogen, halogen (preferably chloro, bromo or iodo), alkyl, alkoxyalkyl of 2 to 7 carbons, hydroxyalkyl of 1 to 6 carbons, or CH2NR6R7;
R6 and R7 are, independently, hydrogen, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms; or, taken together with the nitrogen atom of CH2NR6R7, R6 and R7 form a five or six membered ring optionally containing one or more additional heteroatoms such as, but not limited to, those of the group: 
xe2x80x83R8 is a straight chain alkyl of 1 to 6 carbon atoms
R9 is independently hydrogen, trimethylsilyl or a straight chain alkyl of 1 to 6 carbon atoms;
or a pharmaceutically acceptable salt, ester or prodrug form thereof.
Among the more preferred compounds of this invention are those of the formula: 
wherein:
A and B are, independently, CH or nitrogen;
D is Cxe2x80x94W or nitrogen;
R1 is alkanoyl of 2 to 7 carbon atoms or a group selected from 
xe2x80x83R2, R3 and R5 are, independently, hydrogen, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, or perfluoroalkyl of 1 to 6 carbons;
R4, X, Y, W, R6, R7 and R8 are as defined above;
or a pharmaceutically acceptable salt thereof.
For the compounds defined above and referred to herein, unless otherwise noted, aroyl groups include, for example, benzoyl, naphthoyl which can be substituted independently with one or more substituents from the group of hydrogen, halogen, cyano, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, alkoxy of 1 to 6 carbons, CF3, or phenyl.
Heteroaroyl groups herein refer to a carbonyl (radical ) directly bonded to a carbon atom of a five membered heterocyclic ring having one or two heteroatoms selected from nitrogen, oxygen, sulfur, for example 2-thienoyl. The heterocyclic ring of the heteroaroyl groups may also include, but are not limited to, groups in which the heteroaryl portion is a furan, pyrrole, 2H-pyrrole, imidazole, pyrazole, isothiazole, isoxazole, thiophene, pyrazoline, imidazolidine or pyrazolidine group. The heteroaryl groups herein can be substituted independently with one or more substituents from the group of hydrogen, halogen, cyano, straight chain alkyl of 1 to 6 carbon atoms, or branched chain alkyl of 3 to 7 carbon atoms.
The arylalkanoyl groups herein refer to a carbonyl group or radical directly bonded to an alkyl group of 1 to 6 carbon atoms which is terminally substituted by an aryl group, for example, phenylacetic acid. The aryl group can be substituted independently with one or more substituents from the group of hydrogen, halogen, cyano, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, alkoxy of 1 to 6 carbons, CF3, or phenyl or substituted phenyl where the substituents are selected from halogen, cyano, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, alkoxy of 1 to 6 carbons, CF3.
The halogens referred to herein may be selected from fluorine, chlorine, bromine or iodine, unless otherwise specified.
It is understood by those practicing the art that the definition of the compounds of formula (I), when R1, R2, R3, R4, R5, R6, R7, X, or Y contain asymmetric carbons, encompass all possible stereoisomers and mixtures thereof which possess the activity discussed below. In particular, it encompasses any optical isomers and diastereomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof, which possess the indicated activity. Optical isomers may be obtained in pure form by standard separation techniques. It is also understood that the definition of R1, R2, R3, R4, R5, R6, R7, X, or Y of the compounds of formula (I), encompasses all possible regioisomers, and mixtures thereof which possess the activity discussed below. Such regioisomers may be obtained pure by standard separation methods known to those skilled in the art.
Also among the preferred groups of compounds of this invention are those in the subgroups:
a) compounds having the general formula: 
wherein A, B, W, R1, R2, R3, R4, R5, R6, R7, R8, R9, X, and Y are as defined above;
b) compounds having the general formula: 
wherein A, B, R1, R2, R3, R4, R5, R9, X, and Y, are as defined above; and
c) compounds having the general formula: 
wherein A, B, R1, R2, R3, R4, R5, R9, X, and Y, are as defined above.
It is understood that subgroups a)-c), above, further include subgroups wherein:
A and B are, independently, CH or nitrogen;
R1 is alkanoyl of 2 to 7 carbon atoms or a group selected from 
xe2x80x83R2, R3 and R5 are, independently, hydrogen, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, or perfluoroalkyl of 1 to 6 carbons; and
R4, X, Y, W, R6, R7 and R8 are as defined above;
or a pharmaceutically acceptable salt thereof.
Particularly preferred among the compounds of group a), above, are those in which W is H, A and B are each CH, and R1 is the group of alkanoyl of 2 to 7 carbon atoms or a group selected from the moieties (a), (b), (e), (f), (g), (h), (i) or (k), listed above,.
The pharmaceutically acceptable salts include those derived from such organic and inorganic acids as: lactic, citric, acetic, tartaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and similarly known acceptable acids.
Also according to the present invention there is provided a method of treating diseases, conditions or disorders in which vasopressin agonist activity is desired, the method comprising administering to a human or other mammal in need thereof an effective amount of a compound or a pharmaceutical composition of this invention. The present methods of treatment include those for diseases, conditions or disorders which make it desirable to release factor VIE and von Willebrand factor into the circulatory system, release tissue-type plasminogen activator (t-PA) in the blood circulation, or affect the renal conservation of water and urine concentration. Such methods of treatment include, but are not limited to, treatments for diabetes insipidus, nocturnal enuresis, nocturia, urinary incontinence, or bleeding and coagulation disorders in humans or other mammals.
The methods herein include facilitation in humans or other mammals of temporary delay of urination, which may also be described as controlling or treating the inability to temporarily delay urination, whenever desirable. This method is understood to include treatments facilitating the temporary delay of urination which are separate from and not included in the treatment of the condition known as nocturnal enuresis.
The present invention accordingly provides a pharmaceutical composition useful for treating the abovementioned diseases, conditions or disorders, the pharmaceutical composition comprising one or more compounds, or a pharmaceutically acceptable salt thereof, of this invention in combination or association with a pharmaceutically acceptable carrier.
The compositions are preferably adapted for oral administration. However, they may be adapted for other modes of administration, for example, parenteral administration for patient suffering from heart failure.
In order to obtain consistency of administration, it, is preferred that a composition of the invention is in the form of a unit dose. Suitable unit dose forms include tablets, capsules and powders in sachets or vials. Such unit dose forms may contain from 0.1 to 1000 mg of a compound of the invention and preferably from 2 to 50 mg. Still further preferred unit dosage forms contain 5 to 25 mg of a compound of the present invention. The compounds of the present invention can be administered orally at a dose range of about 0.01 to 100 mg/kg or preferably at a dose range of 0.1 to 10 mg/kg. Such compositions may be administered from 1 to 6 times a day, more usually from 1 to 4 times a day.
The compositions of the invention may be formulated with conventional carriers or excipients such as fillers, disintegrating agents , binders, lubricants, flavoring agents and the like. They are formulated in conventional manner, for example, in a manner similar to that use for known antihypertensive agents, diuretics and xcex2-blocking agents.
Also according to the present invention there are provided processes for producing the compounds of the present invention.
The compounds of the present invention may be prepared according to one of the general processes outlined below.
As shown in Scheme I, a tricyclic benzodiazepine of formula (1) is treated with an appropriately substituted acetylaroyl (heteroaroyl) halide, preferably an aroyl (heteroaroyl) chloride of formula (2) in the presence of a base such as pyridine or a trialkylamine such as triethylamine, in an aprotic organic solvent such as dichloromethane or tetrahydrofuran at temperatures from xe2x88x9240xc2x0 C. to 50xc2x0 C. to yield the acylated derivative of formula (3). Treatment of (3) with a dialkylamide dialkyl acetal of formula (4) in an aprotic organic solvent such as dichloromethane at temperatures ranging from 0xc2x0 C. to the reflux temperature of the solvent yields the enone of formula (5) according to the procedure of Lin et al., J. Het. Chem., 14, 345 (1977). Treatment of (5) with hydroxylamine or a substituted hydrazine of formula (6) in acetic acid at temperatures ranging from ambient to the reflux temperature of the solvent yields the target compounds of formula (I) wherein A, B, D, E, G, X, Y, R2 and R4 are as defined above, and R1 is an heterocyclic moiety selected from the (f), (g), or (j) group of heterocycles defined above. 
The preferred substituted acetylaroyl (heteroaroyl) chlorides of formula (2) of Scheme I are conveniently prepared by treating the corresponding carboxylic acids with thionyl chloride at temperatures ranging from ambient to the reflux temperature of the solvent, or with oxalyl chloride in an aprotic solvent such as dichloromethane or tetrahydrofuran in the presence of a catalytic amount of dimethylformamide at temperatures ranging from 0xc2x0 C. to 40xc2x0 C.
The preferred dialkylamide dialkylacetals are either available commercially, or are known in the literature, or can be conveniently prepared according to procedures analogous to those in the literature. Kantlehner, W. Chem. Ber. 105, 1340 (1972).
The preferred tricyclic benzodiazepines of formula (1) are a 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (Albright et al., U.S. Pat. No. 5,536,718, issued Jul. 16, 1996), a 10,11-dihydro-5H-pyrazole[5,1-c][1,4]benzodiazepine, Cecchi, L. et. al., J. Het. Chem., 20, 871 (1983), and 10,11-dihydro-5H-tetrazole[5, 1-c][1,4]benzodiazepine, Klaubert, D. H., J. Het. Chem., 22, 333 (1985). 
An alternate process for the preparation of intermediates of formula (3) is illustrated in the following Scheme II. 
Thus, a tricyclic benzodiazepine of formula (1) is treated with an appropriately substituted bromo aroyl (heteroaroyl) halide, preferably an aroyl (heteroaroyl) chloride of formula (8) in the presence of an organic base such as pyridine or a trialkylamine such as triethylamine in an aprotic organic solvent such as dichloromethane or tetrahydrofuran at temperatures from 40xc2x0 C. to 50xc2x0 C. to yield the acylated intermediate of formula (9). The intermediate (9) is subsequently coupled with a mono substituted terminal acetylene such as trimethylsilyl or a straight chain alkyl of 1 to 6 carbon atoms, in the presence of pyridine and a catalyst such as bis(triphenylphosphine) palladium (II) chloride and copper (I) iodide in an organic base such as triethylamine as the solvent, in a sealed pressure tube at temperatures ranging from ambient to 100xc2x0 C. essentially according to the procedure of Martinez et al., J. Med. Chem., 35, 620 (1992). The resulting acetylene intermediate of formula (10) is then hydrated by treatment with 1% sulfuric acid in an aprotic organic solvent such as tetrahydrofuran saturated with mercury (II) sulfate at ambient temperature essentially according to the procedure of Reed et al., J. Org. Chem. , 52, 3491(1987) to provide the desired acyl compound of formula (3) wherein A, B, D, E, G, X, and Y, are as defined above and R9 is hydrogen or a straight chain alkyl of 1 to 6 carbon atoms . Alternatively, compound 9 where R9 is trimethylsilyl is treated with tetrabutylammonium fluoride in an ether solvent such as tetrahydrofuran to afford compound (10) where R9 is hydrogen.
The preferred acylating agents of formula (8) of Scheme II are conveniently prepared by treating an appropriately substituted aryl (heteroaryl) carboxylic acid of formula (7) with thionyl chloride at temperatures ranging from ambient to the reflux temperature of the solvent, or with oxalyl chloride in an aprotic organic solvent such as dichloromethane or tetrahydrofuran in the presence of a catalytic amount of dimethylformamide at temperatures ranging from 0xc2x0 C. to 40xc2x0 C.
The protected acetylene intermediates of Scheme II are either available commercially, or are known in the art, or can be readily prepared by procedures analogous to those in the art.
As shown in Scheme III, the intermediate acetyl compounds (3) of Scheme I can be prepared also by the Stille coupling of a bromo aryl (heteroaryl) compound of formula (9) of Scheme II with a (xcex1-ethoxyvinyl)trialkyltin, preferably a (xcex1-ethoxyvinyl)tributylltin, in the presence of a catalytic amount of bis(triphenylphosphine) palladium(II) chloride in an aprotic organic solvent such as toluene at temperatures ranging from ambient to the reflux temperature of the solvent, essentially according to the procedure of Kosugi et al., Bull. Chem. Soc. Jpn., 60, 767 (1987). 
The preparation of the acetyl compound (3) can also be accomplished via a palladium-catalyzed arylation of a vinyl alkyl ether such as vinyl butylether, with the aryl halide intermediate of formula (9) according to the procedure of Cabri et al., Tetrahedron Lett., 32, 1753 (1991).
The (xcex1-alkoxyvinyl)trialkyltin intermediates of Scheme III are either available commercially, or are known in the art, or can be readily prepared by procedures analogous to those in the art.
In the case where R4 in Scheme I is hydrogen, the heterocyclic nitrogen can be alkylated or acylated according to the reactions outlined in Scheme IV. 
Thus, the pyrazole compound of formula (I, R4 is H) is alkylated by treatment with a strong base such as sodium or potassium hydride and an alkylating agent such as an alkyl halide, preferably an alkyl chloride (bromide or iodide) in an aprotic organic solvent such as dimethylformamide or tetrahydrofuran at temperatures ranging from 0xc2x0 C. to 80xc2x0 C. to yield compound (I, R1=(f) or (g)) wherein A, B, D, E, G, X, Y, and R2 are as defined above, and R4 is an alkyl or acyl moiety. Alternatively, compound (I) is acylated by treatment with a carboxylic acid halide, preferably a chloride, or a carboxylic acid anhydride in the presence of an amine base such as pyridine or a trialkylamine, preferably triethylamine, in an aprotic organic solvent such as dichloromethane or tetrahydrofuran with no additional solvent when pyridine is used as the base, at temperatures ranging from xe2x88x9240xc2x0 C. to ambient to yield compound (I) wherein A, B, D, E, G, X, Y and R2 are as defined above, and R4 is an alkyl or acyl moiety. The alkylation or acylation of a compound of formula (I, R4 is H) leads to a mixture of regioisomers wherein R2 is hydrogen and R1 is an heterocyclic moiety selected either from the (f) or (g) group of heterocycles defined above and illustrated below, respectively. 
The compounds of general formula (I) of Scheme I wherein A and B are carbon, R2 is H, and R1 is an heterocyclic moiety selected from the (g) group of heterocycles defined above, can be prepared according to the general process outlined in Scheme V. 
Thus, an appropriately substituted haloaryl (heteroaryl) carboxylic acid ester, preferably a bromo (or iodo) methylester of formula (11) is coupled with a dialkylamino propyne, preferably 1-dimethylamino propyne, in the presence of a catalyst such as bis(triphenylphosphine) palladium(II) chloride and copper(I) iodide in an organic base such as triethylamine as the solvent and at temperatures ranging from ambient to 80xc2x0 C. essentially according to the procedures of Alami et al., Tetrahedron Lett., 34, 6403 (1993), and of Sanogashira et al., Tetrahedron Lett., 4467 (1975) to provide the substituted acetylene intermediate of general formula (12). The intermediate (12) is subsequently converted into its N-oxide by treatment with an oxidizing agent using any of a number of standard oxidative procedures (Albini, A., Synthesis, 263 (1993) or with dioxirane reagents (Murray, R. W., Chem. Rev., 1187 (1989), in an aprotic organic solvent such as dichloromethane at temperatures below ambient. The intermediate N-oxide is not isolated but is rearranged in situ to an enone of general formula (13) by treatment with, preferably with heating, a hydroxylic solvent, including any solvent or combination of solvents composed of or containing water, any C1-C8 straight chain or branched chain alkyl alcohol, ethylene glycol, polyethylene glycol, 1,2-propylene diol, polypropylene glycol, glycerol, 2-methoxyethanol, 2-ethoxyethanol, 2,2,2-trifluoroethanol, benzyl alcohol, phenol, or any equivalent solvent that contains one or more free hydroxyl (xe2x80x94OH) substituent(s) that is known to those skilled in the art.
Solvent systems containing one or more cosolvents, along with one or more solvents may also be used for this process of rearranging the N-oxide to the desired enaminone. The cosolvents referred to herein may be defined as a diluent of the main solvent(s) and can be selected from: hydrocarbons such as pentane, hexane or heptane; aromatic hydrocarbon such as benzene, toluene or xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane or dimethoxy ethane; chlorinated hydrocarbons such as dichloromethane, chloroform, dichloroethane, or tetrachloroethane; or other common solvents such as ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dimethylsulfoxide, acetone, or the like.
The conversion of the amine N-oxide into an enaminone may be accomplished by introducing the amine N-oxide into a suitable hydroxylic solvent, preferably with stirring, at or between about room or ambient temperature and about the reflux temperature of the solvent. In other instances the introduction of the amine N-oxide to a hydroxylic solvent, preferably with stirring, may be accomplished in the presence of an acceptable catalyst, such as a palladium(II) catalyst or a copper (I) catalyst, at or between room temperature and the reflux temperature of the solvent.
This procedure provides a novel synthesis of enaminone compounds from propargylic amines or their N-oxides in hydroxylic solvents, which influence the ultimate outcome of the reaction. This new method of enaminone synthesis provides a convenient alternative to existing methods and further extends the range of starting materials that can be converted into enaminone products.
Although the precise mechanism by which a propargylic amine N-oxide is converted into an enaminone product has not been rigorously determined, it likely resembles two known processes; the thermal [2,3]-sigmatropic rearrangement of propargylic amine N-oxides (Craig, et. al., Tetrahedron Lett., 4025, 1979; Hallstrom, et. al., Tetrahedron Lett., 667, 1980; Khuthier, A-H, et. al., J. Chem. Soc. Chem. Commun., 9, 1979) and the conversion of certain isoxazoles into enaminones (Liguori, et. al., Tetrahedron, 44, 1255, 1988).
Treatment of (13) with a substituted hydrazine (6) in acetic acid at temperatures ranging from ambient to reflux leads to a mixture of regioisomeric compounds of general formulas (14) and (15) in a variable ratio. The major isomer of formula (14) is separated by means of chromatography and/or crystallization and subsequently hydrolyzed to the desired carboxylic acid of formula (16).
The intermediate (16) is then converted into an acylating species, preferably an acid chloride (bromide or iodide) or a mixed anhydride of formula (17) by procedures analogous to those described hereinbefore. The acylating agent (17) is then used to acylate a tricyclic benzodiazepine of formula (1) by any of the procedures described hereinbefore to yield the desired compound of formula (I), wherein A, B are CH and D, E, G, X, Y, and R4 are as defined above, R2 is hydrogen and R1 is a heterocyclic moiety selected from the (g) group of heterocycles illustrated below. 
Likewise, treatment of (13) with an unsubstituted hydrazine (6, R4 is H) in acetic acid at temperatures ranging from ambient to the reflux temperature of the solvent yields the intermediate pyrazole ester of formula (18). In this case the heterocyclic nitrogen can be alkylated or acylated as shown in Scheme VI to provide compounds of formula (I) wherein R2 is hydrogen, and R1 is an heterocyclic moiety selected from the (f) group of heterocycles defined above. 
Thus, the intermediate ester of formula (18) is alkylated by treatment with a strong base such as sodium or potassium hydride and an alkylating agent such as an alkyl halide, preferably an alkyl chloride (bromide or iodide), in an aprotic solvent such as dimethylformamide or tetrahydrofuran at temperatures ranging from 0xc2x0 C. to 80xc2x0 C. to yield a mixture of regioisomers of formulas (14) and (15) in a variable ratio. The major regioisomer of formula (15) is separated by chromatography and/or crystallization and subsequently hydrolyzed to the desired carboxylic acid of formula (19), which is then converted into an acylating agent, preferably an acyl chloride or a mixed anhydride by procedures analogous to those described hereinbefore. The acylating species of formula (20) is then used to acylate a tricyclic benzodiazepine of formula (1) to yield the desired compound of formula (I), wherein A, B, D, E, G, X, Y, and R4 are as defined above, R2 is hydrogen, and R1 is a heterocyclic moiety selected from the (f) group of heterocycles defined above. 
Compounds of general formula (I) wherein R1 is an heterocyclic moiety selected from the (h) group of R1 heterocycles defined above, can be prepared as outlined in Scheme VII. 
An appropriately substituted malondialdehyde of formula (21) is treated first with a hydrazine in acetic acid at temperatures ranging from ambient to the reflux temperature of the solvent and the intermediate pyrazole is then oxidized with potassium permanganate in a basic aqueous solution at temperatures ranging from ambient to the reflux temperature of the solvent to yield a carboxylic acid intermediate of formula (22). The acid (22) is converted into an acylating agent, preferably an acid chloride (bromide or iodide) or a mixed anhydride by procedures analogous to those described hereinbefore. The acylating agent of formula (23) is finally reacted with a tricyclic benzodiazepine of formula (1) to yield compounds of general formula (I) wherein A, B, D, E, G, X, Y, and R4 are as defined above, and R1 is a heterocyclic moiety selected from the (h) group of heterocycles defined above. 
In the case where R4 in Scheme VII is hydrogen, the heterocyclic nitrogen can be alkylated or acylated according to the procedures outlined hereinbefore.
The preferred malondialdehydes of formula (21) and the hydrazines of Scheme VII are either available commercially, or are known in the art, or can be readily prepared by procedures analogous to those in the literature for known compounds, such as those of Knorr et al., J. Org. Chem., 49, 1288 (1984) and Coppola et al., J. Het. Chem., 11, 51 (1974).
An alternative preparation of the intermediate carboxylic acids of formula (22) of Scheme VII wherein Y is as defined above and R4 is other than hydrogen, is outlined in Scheme VIII. 
The organotin reagent of formula (25) is reacted in a Stille coupling reaction with an appropriately substituted aryl (heteroaryl) halide, preferably a bromide or iodide of formula (28) in the presence of a catalyst such as tetrakis(triphenylphosphine)-palladium (0) and copper (I) iodide in an organic aprotic solvent such as dimethylformamide at temperatures ranging from ambient to 150xc2x0 C., essentially according to procedures analogous to those found in Farina et al., J. Org. Chem., 59, 5905 (1994). Basic hydrolysis of the resulting ester of formula (26) with sodium or lithium hydroxide in aqueous alcohol or tetrahydrofuran at temperatures ranging from ambient to the reflux temperature of the solvent yields the desired carboxylic acids of formula (22).
In turn, the organotin reagents of formula (25) wherein the R groups are preferably alkyl groups, are conveniently prepared by metallation of a 4-bromo N-alkylpyrazole of formula (24) with a trialkyltin halide, preferably a tributyltin chloride (or bromide) in the presence of a metallating agent such as an alkyllithium such as n-butyl lithium, sec-butyl lithium, or tert-butyllithium in an aprotic organic solvent such as diethylether at temperatures ranging from xe2x88x9240xc2x0 C. to ambient according to procedures analogous to those found in Martina et al., Synthesis, 8, 613 (1991).
The preferred N-alkyl substituted 4-bromo pyrazoles of formula (24) are conveniently prepared from 4-bromo pyrazole by alkylation with an alkyl halide, preferably an alkyl chloride (bromide or iodide) in the presence of a strong base such as lithium, sodium or potassium hydride in an aprotic organic solvent such as dimethylformamide or tetrahydrofuran at temperatures ranging from 0xc2x0 C. to 80xc2x0 C. Alternatively, alkylation of 4-bromopyrazole can be carried out with an alkylating agent mentioned above, and a strong alkaline base such as lithium, sodium or potassium hydroxide in the presence of a phase transfer catalyst (Jones, R.A. Aldrichimica ACTA, 9(3), 35, 1976) such as benzyldimethyltetradecylammonium chloride, or benzyltrimethylammonium chloride.
The preferred aryl (heteroaryl) iodides of formula (28) are conveniently prepared by diazotization of the corresponding substituted anilines of formula (27) followed by reaction of the corresponding diazonium salt with iodine and potassium iodide in aqueous acidic medium essentially according to the procedures of Street et al., J. Med. Chem., 36, 1529 (1993) and of Coffen et al., J. Org. Chem., 49, 296 (1984).
An alternative preparation of compounds of general formula (I) is outlined in Scheme IX. 
A tricyclic benzodiazepine of formula (1) is treated with an appropriately substituted haloaroyl (heteroaroyl) halide, preferably a fluoro aroyl or a fluoro (or chloro) heteroaroyl chloride of formula (29), in the presence of a base such as triethylamine or diisopropylethylamine in an aprotic organic solvent such as dichloromethane or tetrahydrofuran at temperatures from 40xc2x0 C. to the reflux temperature of the solvent to yield the acylated derivative (30).
Alternatively, the acylating species can be a mixed anhydride of the carboxylic acid described above, such as that prepared by reaction 2,4,6-trichlorobenzoyl chloride in a solvent such as dichloromethane according to the procedure of Inanaga et al., Bull. Chem. Soc. Jpn, 52, 1989 (1979). Treatment of said mixed anhydride of general formula (29) with the tricyclic benzodiazepine of formula (1) in a solvent such as dichloromethane and in the presence of an organic base such as 4-dimethylaminopyridine at temperatures ranging from 0xc2x0 C. to the reflux temperature of the solvent, yields the intermediate acylated derivative (30) of Scheme IX.
A compound of formula (30) is then treated with the lithium, sodium or potassium salt of an appropriately substituted heterocycle of formula (31) in a polar aprotic organic solvent such as dimethylformamide or tetrahydrofuran at temperatures ranging from ambient to the reflux temperature of the solvent to yield a compound of general formula (I), wherein A, B, D, E, G, X, Y, R2, R3, and R5 are as defined above, and R1 is a heterocyclic moiety selected from the group consisting of (a), (b), (c), (d), (l), (n) or (o) defined above. 
The condensation of the intermediate of formula (30) with the intermediate salt of formula (31) leads to a variable ratio of regioisomers of general formula (I) which are separated by means of chromatography and/or crystallization.
The preferred substituted fluoro aroyl and fluoro (or chloro) heteroaroyl chlorides of formula (29) are either available commercially, or are known in the art, or can be readily prepared by procedures analogous to those in the literature for the known compounds.
The lithium, sodium or potassium salts of the heterocycles of formula (31) are prepared by treatment of said heterocycle with a strong base such as lithium hydride, sodium hydride, potassium hydride or a metal alkoxide at temperatures ranging from xe2x88x9240xc2x0 C. to ambient in an aprotic organic solvent such as dimethylformamide or tetrahydrofuran.
Alternatively, the compounds of general formula (I) described in Scheme IX can be prepared according to the process outlined in Scheme X. 
Thus, an appropriately substituted fluoroaryl or fluoro (or chloro)heteroaryl carboxylic acid of formula (32) is esterified using methods known in the art such as treatment with oxalyl chloride (or thionyl chloride) in an alcohol solvent such as methanol, in the presence of a catalytic amount of dimethylformamide; or by condensation with methanol in the presence of an acid catalyst such as para-toluenesulfonic acid at temperatures ranging from ambient to reflux.
The resulting ester of formula (33) is reacted with the lithium, sodium or potassium salt of an appropriately substituted heterocycle of formula (31) in a polar aprotic organic solvent such as dimethylformamide at temperatures ranging from ambient to 150xc2x0 C., to yield an intermediate ester of formula (34). The condensation of (33) with (31) leads to a variable ratio of regioisomers of formula (34) which are separated by means of chromatography and/or crystallization.
Subsequent hydrolysis of the intermediate ester of formula (34) with an aqueous base such as lithium, sodium or lithium hydroxide in methanol or tetrahydrofuran affords the carboxylic acid of formula (35).
The intermediate carboxylic acid (35) is then converted into an acylating agent preferably an acid chloride or a mixed anhydride of general formula (36) using any of the procedures described hereinbefore.
Subsequent reaction of the tricyclic benzodiazepine of formula (1) with the intermediate acylating agent of formula (36) according to any of the procedures described hereinbefore yields the desired compounds of formula (I) of Scheme IX.
Alternatively, the substituted carboxylic acids of formula (35) described in Scheme X can be prepared according to the process outlined in Scheme XI. 
Thus, a fluoro aryl or fluoro (chloro)heteroaryl nitrile of formula (37) is reacted with the lithium, sodium or potassium salt of a substituted heterocycle of formula (31) in an apolar aprotic solvent such as dimethylformamide at temperatures ranging from ambient to 150xc2x0 C., to yield an intermediate of general formula (38). The reaction of (37) with (31) leads to a variable ratio of regioisomers of formula (38) which are separated by means of chromatography and/or crystallization. Hydrolysis of the intermediate nitriles of formula (38, Yxe2x89xa0CF3) is preferentially carried out with an inorganic acid such as sulfuric acid at temperatures ranging from ambient to 60xc2x0 C.
Alternatively, hydrolysis of the nitrite (38) can be carried out by heating in ethanol in the presence of a strong alkaline base such as sodium hydroxide with or without a phase transfer catalyst (Jones, R. A. Aldrichimica Acta, 9(3), 35, 1976,) such as benzyldimethyltetradecyl ammonium chloride.
The resulting carboxylic acids of formula (35) are then converted into the desired compounds of formula (I) of Scheme IX by procedures analogous to those described hereinbefore.
Alternatively, the substituted carboxylic acids of formula (35) of Scheme X can be prepared according to the process outlined in Scheme XII by sequential treatment of a nitrite of formula (38) wherein A and B are CH and where R1 is not alkanoyl of 2 to 7 carbons, alkynyl, (b) or (d), with basic hydrogen peroxide in dimethylsulfoxide essentially according to the procedure of Katritzky et al., Synthesis, 949 (1989), followed by hydrolysis of the resulting amide of formula (38) preferably by treatment with dilute sulfuric acid and sodium nitrite according to the procedure of Hanes et al., Tetrahedron, 51, 7403 (1995). 
Where R1 is not (b) or (d)
A preferred process for the preparation of the intermediate substituted carboxylic acids of formula (35) of Scheme X wherein R1 is a heterocyclic moiety selected from the (a) group of R1 heterocycles defined above, is outlined in Scheme XIII. 
Diazotization of an appropriately substituted aniline of formula (40) followed by reduction of the resulting diazonium salt of formula (41) with tin (II) chloride in concentrated hydrochloric acid according to the procedure of Street et al., J. Med. Chem., 36, 1529 (1993) provides the intermediate hydrazine hydrochloride salt of formula (42). Subsequent condensation of (42) with an aldehyde derivative of formula (47), wherein R2 is as defined above, R3 and R5 is H, and P is dialkylacetal) such as acetylacetaldehyde dimethyl acetal, or a ketone of formula (47), wherein R2, R3 and R5 are as defined above, and P is xe2x95x90O or (O-alkyl)2 in a solvent such as aqueous methanol at temperatures ranging from ambient to 100xc2x0 C. provides after crystallization, the desired intermediate ester of formula (34, R1 is (a) and R5 is H), which is then converted to the compound of formula (I) as outlined in Scheme X above. 
When Y is OCH3 the compounds of general formula (I) of Scheme I can be conveniently demethylated as outlined in Scheme XIV. 
Thus, the reaction of compound (I) wherein Y is OCH3 with boron tribromide in an organic solvent, such as dichloromethane, yields the corresponding phenol of formula (I) wherein Y is OH, and A, B, D, E, G, X, R2 and R3 are as defined above and R1 is an heterocyclic moiety selected from the group (a) of heterocycles defined above and illustrated below. 
Compounds in which R1 contains three heteroatoms are prepared according to Scheme XV. 
Thus, a tricyclic benzodiazepine of formula (1) is treated with an appropriately substituted cyano aroyl (heteroaroyl) halide, preferably an aroyl (heteroaroyl) chloride of formula (43) in the presence of a base in an aprotic organic solvent such as dichloromethane or tetrahydrofuran at temperatures ranging from xe2x88x9240xc2x0 C. to 80xc2x0 C. to yield an intermediate nitrile of formula (46, Scheme XVI) which in turn, is hydrolyzed to an amide intermediate of general formula (44) with an inorganic acid such as sulfuric acid at ambient temperature to 50xc2x0 C. Treatment of the amide (44) with a dialkyl amide dialkyl acetal of formula (4) in an aprotic organic solvent such as dichloromethane or tetrahydrofuran at temperatures ranging from 0xc2x0 C. to 80xc2x0 C. yields the intermediate of formula (45). Treatment of (45) with hydroxylamine or a hydrazine of formula (6) in acetic acid at temperatures ranging from ambient to reflux yields the desired target compounds of formula (I) wherein A, B, D, E, G, X, Y, R2 and R4 are as defined above, and R1 is an heterocyclic moiety selected from the (e), (i) and (k) group of heterocycles defined above. 
Another preferred process for the preparation of the intermediate amide of formula (44), see Scheme XV, wherein A and B are CH and D is not CH is outlined in Scheme XVI and consists of treating a nitrile of formula (46) with basic hydrogen peroxide in dimethylsulfoxide essentially according to the procedure of Katritzky et al., Synthesis, 949 (1989). 
The preferred process to prepare compounds of general formula (I) in which R1 contains four heteroatoms and R4 is hydrogen is outlined in Scheme XVII. 
Treatment of the nitrile intermediate of formula (46) of Scheme XVI with sodium azide and ammonium chloride in an aprotic organic solvent such as dimethylformamide at temperatures ranging from ambient to the reflux temperature of the solvent yields the desired compounds of formula (I) wherein A, B, D, E, G, X, and Y, are as defined above, R4 is hydrogen and R1 is an heterocyclic moiety selected from the group (m) of heterocycles defined above. 
The compounds of general formula (I) wherein D is CW and W is hydrogen, can undergo Mannich condensation as shown in Scheme XVIII. 
Thus, reaction of compounds of formula (I, D is CH) with either aqueous formaldehyde or paraformaldehyde , a substituted amine of formula (47), and glacial acetic acid in an alcohol solvent such as methanol at temperatures ranging from ambient to reflux yields the corresponding Mannich bases of general formula (I), wherein A, B, E, G, X, Y, R2, R3, R5, R6 and R7 are as defined above; D is CW; W is a dialkylaminoalkyl residue preferably a dimethylaminomethyl residue, and R1 is an heterocyclic moiety selected from the (a), (c), (e), (f), (g), (h), (i), A), (k), (l), (m), (n) and (o) group of heterocycles defined above.
Likewise, the compounds of general formula (I) wherein D is CH can undergo halogenation as shown in Scheme XIX. 
Thus, reaction of (I, D is CH) with a N-halosuccinimide such as N-chloro (bromo or iodo)succinimide in a polar aprotic organic solvent such as dichloromethane at temperatures ranging from xe2x88x9280xc2x0 C. to ambient yields the corresponding halogenated derivatives of general formula (I), wherein A, B, E, G, X, R2, R3 and R5 are as defined above, D is CW, W is a halogen such as chlorine (bromine or iodine), and R1 is an heterocyclic moiety selected from the (a), (c), (e), (f), (g), (h), (i), (0), (k), (1), (m), (n) and (o) group of heterocycles defined above.
The subject compounds of the present invention were tested for biological activity according to the following procedures.
Vasopressin V2 Agonist Effects of Test Compounds in Normal Conscious Water-Loaded Rats:
Male or female normotensive Sprague-Dawley rats (Charles River Laboratories, Inc., Kingston, N.Y.) of 350-500 g body weight were supplied with standard rodent diet (Purina Rodent Lab. Chow 5001) and water ad libitum. On the day of test, rats were placed individually into metabolic cages equipped with devices to separate the feces from the urine and containers for collection of urine. Test compound or reference agent was given at an oral dose of 10 mg/kg in a volume of 10 ml/kg. The vehicle used was 20% dimethylsulfoxide (DMSO) in 2.5% preboiled corn starch. Thirty minutes after dosing the test compound, rats were gavaged with water at 30 ml/kg into the stomach using a feeding needle. During the test, rats were not provided with water or food. Urine was collected for four hours after dosing of the test compound. At the end of four hours, urine volume was measured. Urinary osmolality was determined using a Fiske One-Ten Osmometer (Fiske Associates, Norwood, Mass., 02062) or an Advanced CRYOMATIC Osmometer, Model 3C2 (Advanced Instruments, Norwood, Mass.). Determinations of Na+, K+ and Clxe2x88x92 ion were carried out using ion specific electrodes in a Beckman SYNCHRON EL-ISE Electrolyte System analyzer. The urinary osmolality should increase proportionally. In the screening test, two rats were used for each compound. If the difference in the urine volume of the two rats was greater than 50%, a third rat was used.
Vasopressin V2 Agonist Effects of Test Compounds in Normal Conscious Homozygous Brattleboro Rats with Central Diabetes Insipidus
Male or female homozygous Brattleboro rats (Harlan Sprague Dawley, Inc., Indianapolis, Ind.) of 250-350 g body weight were supplied with standard rodent diet (Purina Rodent Lab. Chow 5001) and water ad libitum. On the day of test, rats were placed individually into metabolic cages equipped with devices to separate the feces from the urine and containers for collection of urine. Test compound or reference agent was given at an oral dose of 1 to 10 mg/kg in a volume of 10 ml/kg. The vehicle used was 20% dimethylsulfoxide (DMSO) in 2.5% preboiled corn starch. During the test, rats were provided with water ad libitum. Urine was collected for six hours after dosing of the test compound. At the end of six hours, urine volume was measured. Urinary osmolality was determined using a Fiske One-Ten Osmometer (Fiske Associates, Norwood, Mass., 02062) or an Advanced CRYOMATIC Osmometer, Model 3C2 (Advanced Instruments, Norwood, Mass.). Determinations of Na+, K+ and Clxe2x88x92 ion were carried out using ion specific electrodes in a Beckman SYNCHRON EL-ISE Electrolyte System analyzer. This animal model was mainly used for evaluation of potency and duration of action of the active compounds. The results of this study are shown in Table I.